Endothelin antagonists and their preparation

ABSTRACT

PCT No. PCT/JP92/01405 Sec. 371 Date May 12, 1994 Sec. 102(e) Date May 12, 1994 PCT Filed Oct. 30, 1992 PCT Pub. No. WO93/10144 PCT Pub. Date May 27, 1993A compound of the formula:    &lt;IMAGE&gt;  (I)  in which R3 is hydrogen or lower alkyl, R4 is pyridyl (lower) alkyl; and R1, R2, R5 and A are defined in the description; or a pharmaceutically acceptable salt thereof, which have endothelin antagonistic activity.

This application is the national phase, filed under 37 C.F.R. 1.371 ofPCT/JP92/01405, filed Oct. 30, 1992.

The present invention relates to new compound and a pharmaceuticallyacceptable salt thereof.

More particularly, it relates to new peptide compound and apharmaceutically acceptable salt thereof which have pharmacologicalactivities such as endotheline antagonistic activity and the like, toprocesses for its preparation, to a pharmaceutical compositioncomprising the same, and to a method of using the same therapeuticallyin the treatment and the prevention of endothelin mediated diseases suchas hypertension, and the like.

One object of the present invention is to provide new and useful peptidecompound and a pharmaceutically acceptable salt thereof which havepharmacological activities such as endothelin antagonistic activity andthe like.

Another object of the present invention is to provide processes for thepreparation of said peptide compound and a salt thereof.

A further object of the present invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said peptide compoundor a pharmaceutically acceptable salt thereof.

Still further object of the present invention is to provide a method ofusing the same for the treatment and the prevention of endothelinmediated diseases such as hypertension, and the like.

DISCLOSURE OF INVENTION

The object compound of the present invention can be represented by thefollowing general formula (I). ##STR2## in which R³ is hydrogen or loweralkyl,

R⁴ is pyridyl(lower)alkyl; and

R¹ is C₃ -C₈ alkyleneamino, N,N-di(lower)alkylamino, N-loweralkyl-N-arylamino, N-lower alkyl-N-C₃ -C₈ cycloalkylamino, or C₅ -C₁₀bicyclic alkyleneamino,

R² is lower alkyl,

R⁵ is C₃ -C₈ alkyleneamino, N,N-di(lower)alkylamino, morpholino,thiomorpholino, N',N'-di(lower)alkylhydrazino, morpholinoamino, loweralkylpiperazinylamino, lower alkoxy(lower)alkylamino,morpholino(lower)alkylamino, C₃ -C₈ alkyleneamino(lower)alkylamino whichmay be substituted by oxo, or pyridyl(lower)alkylamino, and

A is lower alkylene; or

R¹ is piperidin-1-yl, lower alkylpiperidin-1-yl, octahydroazocin-1-yl,indolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl, N,N-di(lower)alkylamino,N-lower alkyl-N-arylamino, N-lower alkyl-N-C₃ -C₈ cycloalkylamino, or C₅-C₁₀ bicyclic alkyleneamino,

R² is lower alkyl,

R⁵ is amino or lower alkylamino, and

A is lower alkylene; or

R¹ is piperidin-1-yl, octahydroazocin-1-yl, N,N-di(lower)alkylamino, orC₅ -C₁₀ bicyclic alkyleneamino,

R² is lower alkyl,

R⁵ is amino, lower alkylamino, N,N-di(lower)alkylamino, C₃ -C₈alkyleneamino, or morpholino, and

A is --NH--; or

R¹ is hexahydro-1H-azepin-1-yl,

R² is isobutyl,

R⁵ is ethylamino, and

A is methylene; or

R¹ is N-[1-(dimethylcarbamoyl)-2,2-dimethylpropyl]amino,

R² is isobutyl,

R⁵ is amino, and

A is --NH--; or

R¹ is N,N-di(lower)alkylamino, 1,2,3,4-tetrahydroquinolin-1-yl, N-loweralkyl-N-arylamino, or N-lower alkyl-N-C₃ -C₈ cycloalkylamino,

R² is lower alkyl,

R⁵ is hydroxy or CO--R⁵ is protected carboxy, and

A is lower alkylene; or

R¹ is C₅ -C₁₀ bicyclic alkyleneamino,

R² is lower alkyl,

R⁵ is hydroxy or CO--R⁵ is protected carboxy, and

A is lower alkylene or --NH--; or

R¹ is N-ethyl-N-(1-ethylpropyl)amino, N-ethyl-N-isopropylamino,N-ethyl-N-neopentylamino, or N-(1-ethylpropyl)-N-propylamino,

R² is isobutyl,

R⁵ is hydroxy or CO--R⁵ is protected carboxy, and

A is --NH--; or

R¹ is piperidin-1-yl,

R² is isobutyl,

R⁵ is hydroxy or CO--R⁵ is protected carboxy, and

A is methylene; or

R¹ is hexahydro-1H-azepin-1-yl,

R² is propyl,

R⁵ is hydroxy or CO--R⁵ is protected carboxy, and

A is --NH--;

or a pharmaceutically acceptable salt thereof.

Particularly, the compound represented by the following formula (I') ismore useful as an endothelin antagonist and the like. ##STR3## in whichR¹, R², R⁵ and A are each as defined above.

Suitable examples of each definition for the compound (I) may beexemplified by the preferred embodiments of the compound (I) mentionedbelow.

Preferred embodiments of the definitions of the compound (I) may be:

R² is isobutyl, R⁵ is pyrrolidin-1-yl, A is methylene, and R¹ ispiperidino, hexahydro-1H-azepin-1-yl, octahydroazocin-1-yl,N-methyl-N-cyclohexylamino, N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl or N-neopentyl-N-ethylamino; or

R² is isobutyl R⁵ is pyrrolidin-1-yl, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl, N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl or N-neopentyl-N-ethylamino; or

R² is isobutyl, R⁵ is dimethylamino, A is methylene, and R¹ ispiperidino, hexahydro-1H-azepin-1-yl, octahydroazocin-1-yl,N-methyl-N-phenylamino, N-methyl-N-cyclohexylamino,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl, N-neopentyl-N-ethylamino orN-methyl-N-(o-tolyl)amino; or

R² is isobutyl, R⁵ is dimethylamino, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl, N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl, or N-neopentyl-N-ethylamino; or

R² is isobutyl, R⁵ is ethylamino, A is --NH--, and R¹ is piperidino oroctahydroazocin-1-yl; or

R¹ is hexahydro-1H-azepin-1-yl, R² is isobutyl, R⁵ is ethylamino and Ais methylene; or

R² is isobutyl, R⁵ is morpholino, A is methylene, and R¹ is piperidino,hexahydro-1H-azepin-1-yl, octahydroazocin-1-yl orN-methyl-N-cyclohexylamino; or

R² is isobutyl, R⁵ is morpholino, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl or N-ethyl-N-(1-ethylpropyl)amino; or

R¹ is hexahydro-1H-azepin-1-yl, R² is isobutyl, A is methylene, and R⁵is thiomorpholino, piperidino, N',N'-dimethylhydrazino, morpholinoamino,4-methylpiperazin-1-ylamino, ethylamino, 2-methoxyethylamino,2-morpholinoethylamino, 3-(2-oxopyrrolidin-1-yl)propylamino,2-piperidinoethylamino or 2-(pyridin-2-yl)ethylamino; or

R² is isobutyl, R⁵ is amino, A is methylene, and R¹ is piperidino,octahydroazocin-1-yl, dipropylamino, N-methyl-N-butylamino,N-ethyl-N-butylamino, N-ethyl-N-isopropylamino,N-ethyl-N-(1-ethylpropyl)amino, N-propyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl, N-ethyl-N-neopentylamino,N-methyl-N-cyclohexylamino, N-methyl-N-phenylamino,1,2,3,4-tetrahydroquinolin-1-yl, 4-methylpiperidino or indolin-1-yl; or

R² is isobutyl, R⁵ is amino, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl, N-ethyl-N-(1-ethylpropyl)amino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-neopentylamino,(1-dimethylcarbamoyl-2,2-dimethylpropyl)amino or3-azabicyclo[3.2.2]nonan-3-yl;

R² is isobutyl, R⁵ is methylamino, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl, N-ethyl-N-neopentylamino or3-azabicyclo[3.2.2]nonan-3-yl; or

R² is isobutyl, R⁵ is methylamino, A is methylene, and R¹ is piperidino,octahydroazocin-1-yl or N-methyl-N-cyclohexylamino;

R² is isobutyl, R⁵ is hydroxy, A is methylene, and R¹ is piperidino,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino or 3-azabicyclo[3.2.2]nonan-3-yl; or

R² is isobutyl, R⁵ is hydroxy, A is --NH--, and R¹ isN-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino or 3-azabicyclo[3.2.2]-nonan-3-yl; or

R¹ is hexahydro-1H-azepin-1-yl, R² is propyl, R⁵ is hydroxy and A is--NH--; or

R² is isobutyl, R⁵ is ethoxy, A is methylene, and R¹ is piperidino,N-methyl-N-cyclohexylamino, N-methyl-N-phenylamino,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl or1,2,3,4-tetrahydroquinolin-1-yl; or

R² is isobutyl, R⁵ is ethoxy, A is --NH--, and R¹ isN-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl orN-neopentyl-N-ethylamino; or

R¹ is hexahydro-1H-azepin-1-yl, R² is propyl, R⁵ is ethoxy and A is--NH--.

According to the present invention, the new peptide compound (I) and asalt thereof can be prepared by the processes as shown in the followingschemes. ##STR4## in which R¹, R², R³, R⁴, R⁵ and A are each as definedabove,

CO--R_(a) ⁵ is protected carboxy,

CO--R_(b) ⁵ is carboxy or protected carboxy, and

R_(c) ⁵ is C₃ --C₈ alkyleneamino N,N-di(lower)alkylamino, morpholino,thiomorpholino, N',N'-di(lower)alkylhydrazino, morpholinoamino, loweralkylpiperazinylamino, lower alkoxy(lower)alkylamino,morpholino(lower)alkylamino, C₃ -C₈ alkyleneamino(lower)alkylamino whichmay be substituted by oxo, pyridyl(lower)alkylamino, amino or loweralkylamino.

Some of the starting compounds used in the above Processes are novel andcan be prepared according to the following Methods and/or by theprocedures described in the following Preparations or by a conventionalmanner. ##STR5## in which R¹, R², R³, R⁴, R⁵ and A are each as definedabove,

R⁶ is amino-protective group,

R⁷ is protected carboxy, and

R⁸ is protected carboxy.

Throughout the present specification, the amino acids, peptides,protective groups, condensing agents, etc. are indicated by theabbreviations according to the IUPAC-IUB (Commission on BiologicalNomenclature) which are in common use in a field of this art.

Moreover, unless otherwise indicated, the amino acids and their residueswhen shown by such abbreviations are meant to be L-configured compoundsand residues, while the D-configured compounds and residues are shownwith the prescript of D-.

Suitable pharmaceutically acceptable salts of the object compound (I)may be a conventional non-toxic salt and include an acid addition saltsuch as an organic acid salt (e.g. acetate, trifluoroacetate, maleate,tartrate, fumarate, methanesulfonate, benzenesulfonate, formate,toluenesulfonate, etc.), an inorganic acid salt (e.g. hydrochloride,hydrobromide, hydriodide, sulfate, nitrate, phosphate, etc.), or a saltwith a base such as an amino acid (e.g. arginine, aspartic acid,glutamic acid, etc.), an alkali metal salt (e.g. sodium salt, potassiumsalt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesiumsalt, etc.), an ammonium salt, an organic base salt (e.g. trimethylaminesalt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), or thelike.

In the above and subsequent descriptions of the present specification,suitable examples and illustrations of the various definitions which thepresent invention includes within the scope thereof are explained indetail as follows.

The term "lower" is intended to mean 1 to 6, preferably 1 to 5 carbonatoms, unless otherwise indicated.

Suitable "amino-protective group" may include acyl such as an aliphaticacyl, an aromatic acyl, a heterocyclic acyl and an aliphatic acylsubstituted with aromatic or heterocyclic group(s) derived from acidsuch as carboxylic, carbonic, carbamic, sulfonic acids.

Preferable "amino-protective group" thus defined may be the ones usuallyused in the peptide chemistry, such as t-butoxycarbonyl, and the like.

Suitable "protected carboxy" for CO--R⁵ may include esterified carboxymentioned below.

Preferable "esterified carboxy" can be referred to the ones usually usedin the peptide chemistry, such as lower alkoxycarbonyl, and the like.

The processes for preparing the object compound (I) are explained indetail in the following.

PROCESS 1

The object compound (I) or a salt thereof can be prepared by reactingthe compound (II) or its reactive derivative at the carboxy group, or asalt thereof with the compound (III) or its reactive derivative at theamino group, or a salt thereof.

Suitable reactive derivative at the amino group of the compound (III)may include Schiff's base type imino or its tautomeric enamine typeisomer formed by the reaction of the compound (III) with a carbonylcompound such as aldehyde, ketone or the like; a silyl derivative formedby the reaction of the compound (III) with a silyl compound such asbis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide,bis(trimethylsilyl)urea or the like; a derivative formed by reaction ofthe compound (III) with phosphorus trichloride or phosgene, and thelike.

Suitable salts of the compound (III) and its reactive derivative can bereferred to the acid addition salts as exemplified for the compound (I).

Suitable reactive derivative at the carboxy group of the compound (II)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with acid such as substituted phosphoric acid [e.g.dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuricacid, sulfonic acid [e.g. methanesulfonic acid, etc.], aliphaticcarboxilic acid [e.g. acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.]or aromatic carboxylicacid [e.g. benzoic acid, etc.]; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; or an activated ester [e.g.cyanomethyl ester, methoxymethyl ester, dimethyliminiomethyl [(CH₃)₂ N⁺═CH--] ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesylphenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester,etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (II) to beused.

Suitable salts of the compound (II) and its reactive derivative may be abase salt such as an alkali metal salt [e.g. sodium salt, potassiumsalt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesiumsalt, etc.], an ammonium salt, an organic base salt [e.g. trimethylaminesalt, triethylamine salt, pyridine salt, picoline salt,dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.] or thelike.

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (II) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide;N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carboxiimide;N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide;N,N'-carbonylbis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine; ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; diphenyl phosphorylazide; thionyl chloride;oxalyl chloride; lower alkyl haloformate [e.g. ethylchloroformate,.isopropyl chloroformate, etc.]; triphenylphosphine;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;N-hydroxybenzotriazole;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorusoxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal bicarbonate, tri(lower)alkylamine,pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, orthe like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

PROCESS 2

The object compound (I) or a salt thereof can be prepared by reactingthe compound (V) or its reactive derivative at the carboxy group, or asalt thereof with the compound (IV) or its reactive derivative at theamino or imino group, or a salt thereof.

Suitable salts of the compound (I) and its reactive derivative can bereferred to the ones as exemplified for the compound (III) and thecompound (II), respectively.

Suitable reactive derivative of the compound (IV) can be referred to theones as exemplified for the compound (III).

Suitable salts of the compound (IV) can be referred to acid additionsalts as exemplified for the compound (I).

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

PROCESS 3

The object compound (I-b) or a salt thereof can be prepared bysubjecting the compound (I-a) or a salt thereof to removal reaction ofthe carboxy-protective group in R_(a) ⁵.

Suitable salts of the compounds (I-a) and (I-b) can be referred to theones as exemplified for the compound (I).

This reaction is carried out in accordance with a conventional methodsuch as solvolysis including hydrolysis, reduction or the like.

The solvolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g. sodium, potassium, etc.], an alkaline earth metal[e.g. magnesium, calcium, etc.], the hydroxide or carbonate, orbicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]-non-5-ene,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, orthe like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.],an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuricacid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, etc.].

The removal reaction using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.] or the like, ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform,carbon tetrachloride, tetrahydrofuran, N,N-dimethylformamide, a mixturethereof or any other solvent which does not adversely influence thereaction. A liquid base or acid can be also used as the solvent. Thereaction temperature is not critical and the reaction is usually carriedout under cooling to heating.

The reduction method applicable for the removal reaction may includechemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal [e.g. tin, zinc, iron, etc.] or metallic compound[e.g. chromium chloride, chromium acetate, etc.] and an organic orinorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts [e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.], palladium catalysts [e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.], nickel catalysts[e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobaltcatalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts[e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reducedcopper, Raney copper, Ullman copper, etc.] and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.Additionally, in case that the above-mentioned acid to be used inchemical reduction are in liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent, and other conventional solvent such as diethylether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to heating.

PROCESS 4

The object compound (I-d) or a salt thereof can be prepared by reactingthe compound (I-c) or its reactive derivative at the carboxy group, or asalt thereof with the compound (XII), or a salt thereof.

Suitable salts of the compound (I-c) and its reactive derivative can bereferred to the ones as exemplified for the compound (I) and thecompound (II), respectively.

Suitable salts of the compound (I-d) can be referred to the ones asexemplified for the compound (I).

Suitable salts of the compound (XII) may be acid addition salts asexemplified for the compound (I).

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, column chromatography, reprecipitation, or the like.

The object compound (I) can be transformed into its salt in aconventional manner.

The method for preparing the new starting compounds are explained indetail in the following.

METHOD 1

[Step 1]

The compound (III-a) or a salt thereof can be prepared by reacting thecompound (VII) or its reactive derivative at the carboxy group, or asalt thereof with the compound (VI) or its reactive derivative at theamino group, or a salt thereof.

Suitable salts of the compound (VII) and its reactive derivative can bereferred to the ones as exemplified for the compound (II).

Suitable salts of the compound (VIII) and its reactive derivative can bereferred to the ones as exemplified for the compound (III).

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

[Step 2]

The compound (III) or a salt thereof can be prepared by subjecting thecompound (III-a) or a salt thereof to a removal reaction of theamino-protective group of R⁶ in a conventional manner such as thoseexplained in Process 3.

METHOD 2

[Step 1]

The compound (IX) or a salt thereof can be prepared by reacting thecompound (VIII) or its reactive derivative at the carboxy group, or asalt thereof with the compound (IV) or its reactive derivative at theamino or imino group, or a salt thereof.

Suitable salts of the compound (VIII) or its reactive derivative can bereferred to the ones as exemplified for the compound (II).

In case that the symbol "A" is --NH--, the reactive derivative of thecompound (VIII) may also include isocyanates thereof.

Suitable salts of the compound (IX) can be referred to the ones asexemplified for the compound (I).

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

[Step 2]

The compound (II) or a salt thereof can be prepared by subjecting thecompound (IX) or a salt thereof to a removal reaction of thecarboxy-protective group on R⁷ in a conventional manner such as thoseexplained in Process 3.

Suitable salts of the compound (II-a) may be the same as those for thecompound (II).

METHOD 3

[Step 1]

The compound (XI) or a salt thereof can be prepared by reacting thecompound (X) or its reactive derivative at the carboxy group, or a saltthereof with the compound (III) or its reactive derivative at the aminogroup, or a salt thereof.

Suitable salts of the compound (X) or its reactive derivative can bereferred to the ones as exemplified for the compound (II).

Suitable salts of the compound (XI) can be referred to the ones asexemplified for the compound (I).

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction conditions [e.g.reactive derivatives, solvents, reaction temperature, etc.] of thisreaction are to be referred to those as explained in Process 1.

[Step 2]

The compound (V) or a salt thereof can be prepared by subjecting thecompound (XI) or a salt thereof to a removal reaction of thecarboxy-protective group on R⁸ in a conventional manner such as thoseexplained in Process 3.

It is to be noted that the compound (I) and the other compounds mayinclude one or more stereoisomers due to asymmetric carbon atoms, andall of such isomers and mixture thereof are included within the scope ofthis invention.

The object compound (I) and a pharmaceutically acceptable salt thereofhave pharmacological activities such as endothelin antagonisticactivity, for example, relaxating activity of blood vessel, and thelike, and useful for therapeutical treatment and prevention ofendothelin mediated diseases such as hypertension, heart disease such asangina pectoris, cardiomyopathy, myocardial infarction or the like,cerebral stroke such as cerebral arterial spasm, cerebral ischemia,cerebrovascular twitch or the like, late phase cerebral spasm aftersubarachnoid hemorrhage, asthma such as bronchoconstriction or the like,renal failure such as acute renal failure, renal insufficiency caused bypharmaceuticals (e.g. Cisplatin, Cyclosporins, etc.), peripheralcirculatory failure, such as Raynaud's disease, Buerger's disease, etc.,arteriosclerosis, diabetic nephropathy, diabetic retinopathy, shock suchas hemorrhagic shock, shock induced by endotoxins, etc.,hemangioendothelioma, organopathy after re-perfusion [e.g. after organand tissue transplantation, percutaneous transluminal coronaryangiopathy (PTCA), or percutaneous transluminal coronary recanalization(PTCR), etc.], bloodstream disturbance after an operation, ulcer,irritable bowel syndrome (IBS), dysuria, retionopathy, dysmenorrheal,premature birth such as premature labor, threatened abortion, or thelike, glaucoma, re-occlusion after operation of PTCA, and the like.

For therapeutic purpose, the peptide compound (I) and a pharmaceuticallyacceptable salt thereof of the present invention can be used in a formof pharmaceutical preparation containing one of said compounds, as anactive ingredient, in admixture with a pharmaceutically acceptablecarrier such as an organic or inorganic solid or liquid excipientsuitable for oral, parenteral or external administration.

Especially, the peptide compound (I) of this invention is suitable fororal administration.

The pharmaceutical preparations may be capsules, tablets, dragees,granules, solution, suspension, emulsion, sublingual tablet,suppositories, ointment, aerosol, infusion, ophthalmic solutions,vaginal suppository, and the like. If desired, there may be included inthese preparations, auxiliary substances, stabilizing agents, wetting oremulsifying agents, buffers and other commonly used additives.

While the dosage of the compound (I) will vary depending upon the ageand condition of the patient, in the case of intravenous administration,a daily dose of 0.01-100 mg of the active ingredient per kg weight ofhuman being, in the case of intramuscular administration, a daily doseof 0.05-100 mg of the same per kg weight of human being, in case of oraladministration, a daily dose of 0.1-100 mg of the same per kg weight ofhuman being is generally given for the treatment of endothelin-mediateddiseases.

In order to illustrate the usefulness of the object compound (I), thepharmacological test datum of a representative compound of the compound(I) is shown in the following.

Test 1

Radioligand binding assay:

(1) Test Compound

a. Compound A [The compound of Example 65]

(2) Test Method

(a) Crude receptor membrane preparation:

Porcine aorta was purchased from Pel-Freez Biologicals (U.S.A.) andstored at -80° C. until use.

Porcine aorta (50 g) was thawed and dissected free from fatty tissue,minced with scissors and then homogenized with a polytron (BrinkmannPT-20, maximal speed for 3×10 sec) in 100 ml buffer (0.25M sucrose, 10mM Tris-HCl, 0.1 mM EDTA).

The homogenate was centrifuged at 10,000 g for 20 minutes at 4° C.

The supernatant, containing the plasma membrane fraction, wascentrifuged at 100,000 g for 60 minutes at 4° C., and then resultantpellets were referred to as crude membrane fractions.

The pellets were resuspended in 25 ml of binding assay buffer (50 mMTris-HCl, 100 mM NaCl, 5 mM MgCl₂, 1.5 μg/ml phenylmethylsulfonylfluoride (PMSF), 120 μg/ml bacitracin, 12 μg/ml leupepcin, 6 μg/mlchymostain, 0.1% bovine serum albumin (BSA), pH 7.5).

The aorta membrane fractions were stored at -80° C. until use.

(b) ¹²⁵ I-endothelin-1 binding assay:

¹²⁵ I-Endothelin-1 (1.67×10⁻¹¹ M) (Amersham Japan, specific activity:2000 Ci/m mol) was incubated with 50 μl of aorta membrane preparation inbinding assay buffer at room temperature (20°-22° C.) for 60 minutes ina final volume of 250 μl.

After incubation, the incubation mixture were filtered throughGlass-fiber GF/C filter (pretreated with 0.1% polyethylene imine for 3hours prior to use) using cell harvester (Brandel M-24S). The filterswere then washed ten times with a total of 3 ml of the washing buffer(50 mM Tris-HCl, pH 7.5) at 0° C. The filters were counted in a gammacounter (Packard Auto Gamma Model 5650).

(3) Test Results

The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Effect on specific binding of                                                 .sup.125 I-endothelin-1 in porcine aorta membrane                             Test Compound   IC.sub.50 (M)                                                 ______________________________________                                        A               5.2 × 10.sup.-9                                         ______________________________________                                    

From the result of the above-mentioned test, it is clear that compound(I) has endothelin antagonistic activity, therefore are useful for thetreatment and prevention of endothelin mediated diseases, for example,hypertension, heart disease such as angina pectoris, cardiomyopathy,myocardial infarction or the like, cerebral stroke such as cerebralarterial spasm, cerebral ischemia, cerebrovascular twitch or the like,late phase cerebral spasm after subarachnoid hemorrhage, asthma such asbronchoconstriction or the like, renal failure such as acute renalfailure, renal insufficiency caused by pharmaceuticals (e.g. Cisplatin,Cyclosporins, etc.), or the like.

The following examples are given for purpose of illustrating the presentinvention in detail.

In these examples, there are employed the following abbreviations.

Ac: acetyl

Boc: t-butoxycarbonyl

Bu: butyl

Bzl: benzyl

DMF: dimethylformamide

DMSO: dimethyl sulfoxide

Et: ethyl

HOBT: N-hydroxybenzotriazole

Me: methyl

NMM: N-methylmorpholine

Pac: phenacyl

D-Pya: D-(2-pyridyl)alanine

D-4Pya: D-(4-pyridyl)alanine

TFA: trifluoroacetic acid

TEA: triethylamine

TS or Tos: tosyl

WSCD: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

Z: benzyloxycarbonyl

DMAP: dimethylaminopyridine

r.t.: room temperature

Preparation 1-1)

To a mixture of Boc-D-Py-OH (3.00 g), pyrrolidine (0.802 g) and HOBT(1.68 g) in DMF (30 ml) was added WSCD-HCl (2.38 g) under ice-bathcooling. The mixture was stirred overnight at 5° C. The resultingsolution was diluted with ethyl acetate (100 ml) and washed withsaturated sodium bicarbonate (100 ml×2) and brine (100 ml). The organiclayer was dried over magnesium sulfate, and concentrated under reducedpressure. The residue was triturated with isopropyl ether to giveBoc-D-Pya-pyrrolidineamide (2.35 g).

mp: 60°-67° C. Rf: 0.31 (MeOH:CHCl₃ =1:9)

Preparation 1-2)

A solution of Boc-D-Pya-pyrrolidineamide (2.35 g, 7.36 mmol) in TFA (25ml) was stirred for 1.5 hours at r.t. The solution was concentratedunder reduced pressure. The residue was dissolved in chloroform (150 ml)and saturated aqueous sodium bicarbonate (100 ml) was added to thesolution. The layers were separated, and the aqueous layer was extractedwith chloroform (100 ml×3). The organic layer were combined and washedwith brine. The solution was dried over magnesium sulfate andconcentrated under reduced pressure to give H-D-Pya-pyrrolidineamide(1.68 g), as a yellow oil.

Rf: 0.06 (MeOH:CHCl₃ =1:9)

Preparation 1-3)

To a mixture of Boc-D-Trp(Me)-OH (2.72 g), H-D-Pya-pyrrolidineamide(1.88 g) and HOBT (1.27 g) in DMF (30 ml) was added WSCD.HCl (1.80 g)under ice-bath cooling. After being stirred for 2.5 hours at 0° C., themixture was diluted with ethyl acetate (100 ml), and washed withsaturated aqueous sodium bicarbonate (100 ml×2) and brine (100 ml). Theorganic layer was dried over magnesium sulfate, and concentrated underreduced pressure to give Boc-D-Trp(Me)-D-Pya-pyrrolidineamide (4.25 g)as a light yellow oil.

Rf: 0.52 (MeOH:CHCl₃ =1:9)

This product was used in a next step without further purification.

Preparation 1-4)

A solution of Boc-D-Trp(Me)-D-Pya-pyrrolidineamide (4.25 g) in TFA (50ml) was stirred for 1.5 hours at 0° C. TFA was removed in vacuo, and theresidue was dissolved in 4N.HCl--AcOEt (50 ml). The mixture wasconcentrated under reduced pressure. The residue was pulverized withether (25 ml) to give 2HCl.H-D-Trp(Me)-D-Pya-pyrrolidineamide (4.08 g)as a white powder.

Rf: 0.07 (MeOH:CHCl₃ =1:9)

Preparation 2-1)

To a solution of benzyl (2R)-2-(carboxymethyl)-4-methylvalerate (500 mg)in dry dichloromethane (10 ml) was added oxalyl chloride (0.2 ml) at 0°C. After the solution was stirred at the same temperature for 1 hour,the solvent was evaporated in vacuo to give benzyl(2R)-2-(chloro-carbonylmethyl)-4-methylvalerate (522 mg) as an oil.

This product was used in a next step without further purification.

Preparation 2-2)

To a mixture of piperidine (0.281 g) and triethylamine (0.304 g) indichloromethane (10 ml) was added dropwise a solution of benzyl(2R)-2-(chlorocarbonylmethyl)-4-methylvalerate (0.816 g) indichloromethane (5 ml). The solution was stirred at room temperature for30 minutes and the solvent was evaporated in vacuo. The residue wasdissolved in ethyl acetate (30 ml), and washed with 7% hydrochloricacid, saturated aqueous sodium bicarbonate solution, and saturatedaqueous sodium chloride solution successively. The organic layer wasdried over magnesium sulfate, and concentrated in vacuo to give benzyl(2R)-2-(piperidinocarbonylmethyl)-4-methylvalerate (0.931 g) as an oil.

Rf: 0.23 (n-hexane:EtOAc=3:1)

Preparation 2-3)

A solution of benzyl (2R)-2-(piperidinocarbonylmethyl)-4-methylvalerate(0.625 g) in methanol (10 ml) was hydrogenated over 10% palladium oncarbon (80 mg) at 3 atmospheric pressure of hydrogen for 1 hour. Afterremoval of the catalyst by filtration, the filtrate was concentrated invacuo to give (2R)-2-(piperidinocarbonylmethyl)-4-methylvaleric acid(0.43 g) as an oil.

Rf: 0.38 (MeOH:CHCl₃ =1:10)

Preparation 3-1)

Boc-D-Pya-dimethylamide (2.26 g) was obtained in substantially the samemanner as that of Preparation 1-1).

Rf: 0.74 (CHCl₃ :MeOH:AcOH=8:1:1)

Preparation 3-2)

H-D-Pya-dimethylamide was obtained in substantially the same manner asthat of Preparation 1-2).

Rf: 0.06 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 3-3)

Boc-D-Trp(Me)-D-Pya-dimethylamide was obtained in substantially the samemanner as that of Preparation 1-3).

Rf: 0.52 (MeOH:CHCl₃ =1:9), 0.42 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 3-4)

2HCl.H-D-Trp (Me)-D-Pya-dimethylamide was obtained in substantially thesame manner as that of Preparation 11-3).

Rf: 0.07 (MeOH: CHCl₃ =1:9)

Preparation 4-1)

Boc-D-Pya-ethylamide was obtained in substantially the same manner asthat of Preparation 7-1).

mp: 110°-113° C. Rf: 0.36 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 4-2)

H-D-Pya-ethylamide.2HCl was obtained in substantially the same manner asthat of Preparation 11-3).

mp: 193°-194° C. Rf: 0.07 (CHCl₃ :MeOH=9:1)

Preparation 4-3)

Boc-D-Trp(Me)-D-Pya-ethylamide was obtained in substantially the samemanner as that of Preparation 1-3).

mp: 148°-150° C. Rf: 0.60 (CHCl₃ :MeOH=9:1)

Preparation 4-4)

H-D-Trp(Me)-D-Pya-ethylamide.2HCl was obtained in substantially the samemanner as that of Preparation 1-2), except for the presence of anisoleas a cation trapping agent.

mp: 105°-110° C. Rf: 0.06 (CHCl₃ :MeOH=9:1)

Preparation 5-1)

Boc-D-Pya-morpholineamide was obtained in substantially the same manneras that of Preparation 1-1).

Rf: 0.38 (MeOH:CHCl₃ =1:9)

Preparation 5-2)

H-D-Pya-morpholineamide was obtained in substantially the same manner asthat of Preparation 1-2).

Rf: 0.05 (MeOH:CHCl₃ =1:9)

Preparation 5-3)

Boc-D-Trp(Me)-D-Pya-morpholineamide was obtained in substantially thesame manner as that of Preparation 1-3).

mp: 85°-93° C. Rf: 0.51 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 5- 4)

2HCl.H-D-Trp(Me)-D-Pya-morpholineamide was obtained in substantially thesame manner as that of Preparation 11-3).

Rf: 0.03 (MeOH: CHCl₃ =1:9)

Preparation 6-1)

Boc-D-Pya-thiomorpholineamide was obtained in substantially the samemanner as that of Preparation 1-1).

mp: 65°-69° C. Rf: 0.29 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 6-2)

H-D-Pya-thiomorpholineamide was obtained in substantially the samemanner as that of Preparation 2-2).

Rf: 0.07 (CHCl₃ MeOH:AcOH=16:1:1)

Preparation 6-3)

Boc-D-Trp(Me)-D-Pya-thiomorpholineamide was obtained in substantiallythe same manner as that of Preparation 2-3).

mp: 90°-95° C. Rf: 0.31 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 6-4)

2HCl.H-D-Trp(Me)-D-Pya-thiomorpholineamide was obtained in substantiallythe same manner as that of Preparation 11-3).

Rf: 0.04 (MeOH:CHCl₃ =1:9)

Preparation 7-1)

To a solution of Boc-D-Pya-OH (0.20 g) in DMF (4 ml) were addedpiperidine (70 mg), diphenylphosphoryl azide (DPPA) (0.23 g) andtriethylamine (76 mg) at room temperature. After being stirred overnightat room temperature, the mixture was diluted with ethyl acetate andwashed with water, aqueous sodium bicarbonate and brine, successively.The organic layer was dried over magnesium sulfate and concentrated invacuo to give Boc-D-Pya-piperidineamide (0.22 g) as an oil.

Rf: 0.59 (CHCl₃ :MeOH=9:1)

Preparation 7-2 )

H-D-Pya-piperidineamide.2HCl was obtained in substantially the samemanner as that of Preparation 11-3).

Rf: 0.30 (CHCl₃ :MeOH: AcOH=8:2:1)

Preparation 7-3)

Boc-D-Trp(Me)-D-Pya-piperidineamide was obtained in substantially thesame manner as that of Preparation 1-3).

Rf: 0.80 (CHCl₃ :MeOH:AcOH=8:2:1)

Preparation 7-4)

H-D-Trp(Me)-D-Pya-piperidineamide.2HCl was obtained in substantially thesame manner as that of Preparation 4-4).

Rf: 0.11 (CHCl]:MeOH=9:1)

Preparation 8-1)

Boc-D-Pya-N,N-dimethylhydrazide was obtained in substantially the samemanner as that of Preparation 1-1).

Rf: 0.39 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 8-2)

H-D-Pya-N,N-dimethylhydrazide was obtained in substantially the samemanner as that of Preparation 1-2).

Rf: 0.06 (MeOH:CHCl₃ =1:9)

Preparation 8-3)

Boc-D-Trp(Me)-D-Pya-N,N-dimethylhydrazide was obtained in substantiallythe same manner as that of Preparation 1-3).

Rf: 0.34 (MeOH: CHCl₃ =1:9)

Preparation 8-4)

3HCl.H-D-Trp(Me)-D-Pya-N,N-dimethylhydrazide was obtained insubstantially the same manner as that of Preparation 11-3).

Rf: 0.05 (MeOH:CHCl₃ =1:9)

Preparation 9-1)

Boc-D-Pya-(N-morpholino)amide was obtained in substantially the samemanner as that of Preparation 1-1).

Rf: 0.33 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 9-2)

H-D-Pya-(N-morpholino)amide was obtained in substantially the samemanner as that of Preparation 1-2).

Rf: 0.06 (MeOH:CHCl₃ =1:9)

Preparation 9-3)

Boc-D-Trp(Me)-D-Pya-(N-morpholino) amide was obtained in substantiallythe same manner as that of Preparation 1-3).

Rf: 0.43 (MeOH:CHCl₃ =1:9)

Preparation 9-4)

3HCl.H-D-Trp(Me)-D-Pya-(N-morpholino)amide was obtained in substantiallythe same manner as that of Preparation 11-3).

Rf: 0.05 (MeOH:CHCl₃ =1:9)

Preparation 10-1)

Boc-D-Trp(Me)-D-Pya-NH₂ was obtained in substantially the same manner asthat of Example 74.

mp: 162°-163° C. Rf: 0.47 (CHCl₃ :MeOH=9:1)

Preparation 10-2)

2HCl-H-D-Trp(Me)-D-Pya-NH₂ was obtained in substantially the same manneras that of Preparation 4-4).

Rf: 0.05 (MeOH:CHCl₃ =1:9)

Preparation 11-1)

(2R)-2-[(tert-Butyloxycarbonyl)methyl]-4-methylvaleric acid was obtainedin substantially the same manner as that of Preparation 2-3).

Rf: 0.40 (hexane:AcOEt =2:1)

Preparation 11-2)

[(2R)-2-{(tert-Butyloxycarbonyl)methyl}-4-methylvaleryl]-D-Trp(Me)-D-Pya-NH₂was obtained in substantially the same manner as that of Preparation4-3).

mp: 125°-131° C. Rf: 0.47 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 11-3)

A solution of[(2R)-2-{(tert-butyloxycarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-NH₂(3.05 g) in 4N.HCl--AcOEt (50 ml) was stirred for 1.5 hours at 0° C. Themixture was evaporated to give[(2R)-2-(carboxymethyl)-4-methylvaleryl]-D-Trp(Me)-D-Pya-NH₂-hydrochloride (2.48 g).

Rf: 0.17 (CHCl₃ :MeOH:AcOH=8:1:1)

Preparation 12-1)

Benzyl (2R)-2-[N-ethyl-N-(1-ethylpropyl)carbamoyl]-methyl-4-methylvalerate wasobtained in substantially the same manner as that of Preparation 2-2).

Rf: 0.45 (MeOH: CHCl₃ =1:10)

Preparation 12-2)

(2R)-2-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleric acidwas obtained in substantially the same manner as that of Preparation2-3).

Rf: 0.54 (MeOH:CHCl₃ =1:10)

Preparation 13-1)

Benzyl (2R)-2-[(N-methyl-N-cyclohexylcarbamoyl)methyl]-4-methylvaleratewas obtained in substantially the same manner as that of Preparation2-2).

Rf: 0.31 (n-hexane:EtOAc=3:1)

Preparation 13-2)

(2R)-2-[(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleric acid wasobtained in substantially the same manner as that of Preparation 2-3).

Rf: 0.52 (benzene:EtOAc:AcOH=20:20:1)

Preparation 14-1)

Benzyl (2R)-2-[(N-methyl-N-phenylcarbamoyl)methyl]-4-methylvalerate wasobtained in substantially the same manner as that of Preparation 2-2).

Rf: 0.32 (n-hexane:EtOAc=3:1)

Preparation 14-2)

(2R)-2-[(N-Methyl-N-phenylcarbamoyl)methyl]-4-methylvaleric acid wasobtained in substantially the same manner as that of Preparation 2-3).

Rf: 0.50 (benzene:EtOAc:AcOH=20:20:1)

Preparation 15-1)

Benzyl(2R)-2-[(1,2,3,4-tetrahydroquinolin-1-ylcarbonyl)methyl]-4-methylvaleratewas obtained in substantially the same manner as that of Preparation2-2).

Rf: 0.85 (MeOH:CHCl₃ =1:10), 0.38 (hexane:AcOEt =3:1)

Preparation 15-2)

(2R)-2-[1,2,3,4-Tetrahydroquinolin-1-ylcarbonyl)-methyl-4-methylvalericacid was obtained in substantially the same manner as that ofPreparation 2-3).

Rf: 0.40 (MeOH:CHCl₃ =1:9)

Preparation 16

To a solutionof(2R)-2-[(N-ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvalericacid (421 mg) and pyridine (123 mg) in acetonitrile (6 ml) was addeddisuccinimidoylcarbonate (600 mg). The suspension was stirred at roomtemperature overnight to give a clear solution. The solvent wasevaporated in vacuo. The residue was dissolved in ethyl acetate (30 ml),washed with 10% aqueous citric acid solution, saturated aqueous sodiumbicarbonate solution, and saturated aqueous sodium chloride solutionsuccessively, dried over magnesium sulfate, and concentrated in vacuo togive (2R)-2-[N-ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvalericacid succinimido ester (572 mg) as an oil.

Rf: 0.62 (MeOH:CHCl₃ =1:10)

Preparation 17-1)

Benzyl (2R)-2-(N-ethyl-N-isopropylcarbamoyl)methyl-4-methylvalerate wasobtained in substantially the same manner as that of Preparation 2-2).

Rf: 0.36 (n-hexane:EtOAc=2:1)

Preparation 17-2)

(2R)-2-(N-Ethyl-N-isopropylcarbamoyl)methyl-4-methylvaleric acid wasobtained in substantially the same manner as that of Preparation 2-3).

Rf: 0.51 (MeOH:CHCl₃ =1:10)

Preparation 17-3)

(2R)-2-(N-Ethyl-N-isopropylcarbamoyl)methyl-4-methylvaleric acidsuccinimido ester was obtained in substantially the same manner as thatof Preparation 16.

Rf: 0.64 (MeOH:CHCl₃ =1:10)

Preparation 18-1)

Benzyl(2R)-2-[N-propyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvalerate wasobtained in substantially the same manner as that of Preparation 2-2).

Rf: 0.54 (n-hexane:EtOAc =2:1)

Preparation 18-2)

(2R)-2-[N-Propyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleric acidwas obtained in substantially the same manner as that of Preparation2-3).

Rf: 0.58 (benzene:EtOAc:AcOH=20:20:1)

Preparation 18-3)

(2R)-2-[N-Propyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleric acidsuccinimido ester was obtained in substantially the same manner as thatof Preparation 17-3).

Rf: 0.70 (MeOH:CHCl₃ =1:10)

Preparation 19-1)

Benzyl (2R)-2-[N-methyl-N-(o-tolyl)carbamoyl]methyl-4-methylvalerate wasobtained in substantially the same manner as that of Preparation 2-2).

Rf: 0.47 (n-hexane:EtOAc=2:1)

Preparation 19-2)

(2R)-2-[N-Methyl-N-(o-tolyl)carbamoyl]methyl-4-methylvaleric acid wasobtained in substantially the same manner as that of Preparation 2-3).

Rf: 0.49 (benzene:EtOAc:AcOH=20:20:1)

Preparation 19-3)

(2R)-[N-Methyl-N-(o-tolyl)carbamoyl]methyl-4-methylvaleric acidsuccinimido ester was obtained in substantially the same manner as thatof Preparation 17-3).

Rf: 0.56 (MeOH:CHCl₃ =1:10)

Preparation 20-1)

Benzyl(2R)-2-[(3-azabicyclo[3.2.2]nonan-3-yl)carbonylmethyl]-4-methylvaleratewas obtained in substantially the same manner as that of Preparation2-2).

Rf: 0.67 (EtOAc:hexane=1:2)

Preparation 20-2)

(2R)-2-[(3-Azabicyclo[3.2.2]nonan-3-yl)carbonylmethyl]-4-methylvalericacid was obtained in substantially the same manner as that ofPreparation 2-3).

Rf: 0.43 (CHCl₃ :MeOH=9:1)

Preparation 20-3)

(2R)-2-[(3-Azabicyclo[3.2.2 ]nonan-3-yl)carbonylmethyl]-4-methylvalericacid succinimido ester was obtained in substantially the same manner asthat of Preparation 17-3).

This product was used in the next step immediately.

Preparation 21-1)

Benzyl (2R)-2-[(N-neopentyl-N-ethylcarbamoyl)methyl]-4-methylvaleratewas obtained in substantially the same manner as that of Preparation2-2).

Rf: 0.76 (EtOAc:hexane=1:2)

Preparation 21-2)

(2R)-2-[(N-Neopentyl-N-ethylcarbamoyl)methyl]-4-methylvaleric acid wasobtained in substantially the same manner as that of Preparation 2-3).

Rf: 0.38 (CHCl₃ :MeOH=9:1)

Preparation 21-3)

(2R)-2-[(N-Neopentyl-N-ethylcarbamoyl)methyl]-4-methylvaleric acidsuccinimido ester was obtained in substantially the same manner as thatof 17-3).

This product was used in the next step immediately.

Preparation 22-1)

A solution of acetaldehyde (2.53 g) in dioxane (10 ml) was added slowlyto a solution of (1-ethylpropyl)amine (5 g) in dioxane (30 ml). Thesolution was stirred at room temperature for 30 minutes and hydrogenatedover 10% palladium on carbon (0.8 g) at 3 atmospheric pressure ofhydrogen for 4 hours. After removal of the catalyst by filtration, tothe filtrate was added dropwise a solution of di-tert-butyl bicarbonate(12.52 g) in dioxane (20 ml). After being stirred for 30 minutes, thesolution was evaporated in vacuo. The residue was dissolved in ethylacetate, washed with 3% hydrochloric acid, saturated aqueous sodiumbicarbonate solution, and saturated aqueous sodium chloride solutionsuccessively, dried over magnesium sulfate, and concentrated in vacuo.The residue was purified with silica gel column chromatography(n-hexane:ethyl acetate=10:1 as eluent) to giveN-tert-butylcarbonyl-N-ethyl-(1-ethylpropyl)amine (7.05 g). This productwas dissolved in 4N hydrogen chloride in ethyl acetate (70 ml). Afterbeing stirred at room temperature for 30 minutes, the solvent wasevaporated in vacuo. The crystalline residue was washed with ethyl etherto give N-ethyl-N-(1-ethylpropyl)amine hydrochloride (3.66 g).

mp: 142°-143° C.

Preparation 22-2)

To a solution of N-ethyl-N-(1-ethylpropyl)amine hydrochloride (1,517 g)and triethylamine (1.113 g) in dichloromethane (30 ml) was addeddropwise a solution of (S)-α-benzyloxycarbonyl-γ-methylbutyl isocyanate(2.472 g) in dichloromethane (10 ml). The solution was stirred at roomtemperature for 30 minutes and concentrated in vacuo. The residue wasdissolved in ethyl acetate (50 ml) and washed with 7% hydrochloric acid,saturated aqueous sodium bicarbonate solution, and saturated aqueoussodium chloride solution successively. The organic layer was dried overmagnesium sulfate and concentrated in vacuo. The residue was purifiedwith silica gel column chromatography (EtOAc:n-hexane=1:6 as eluent) togive N-[N-ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-OBzl (2.61 g) as anoil.

Rf: 0.40 (EtOAc:n-hexane=1:3)

Preparation 22-3)

N-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-OH was obtained insubstantially the same manner as that of Preparation 2-3).

mp: 56°-57° C. Rf: 0.40 (n-hexane:EtOAc=3:1)

Preparation 23-1)

N-Propyl-N-(1-ethylpropyl)amine hydrochloride was obtained insubstantially the same manner as that of Preparation 22-1).

mp: 138° C.

Preparation 23-2)

N-[N-Propyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-OBzl was obtained insubstantially the same manner as that of Preparation 22-2).

Rf: 0.48 (n-hexane:EtOAc=2:1)

Preparation 23-3)

N-[N-Propyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-OH was obtained insubstantially the same manner as that of Preparation 2-3).

mp: 67°-68° C. Rf: 0.51 (benzene:EtOAc:AcOH=20:20:1)

Preparation 24-1)

N-(N-Isopropyl-N-ethylcarbamoyl)-L-Leu-OBzl was obtained insubstantially the same manner as that of Preparation 22-2).

Rf: 0.43 (EtOAc:hexane=1:2)

Preparation 24-2)

N-(N-Isopropyl-N-ethylcarbmoyl)-L-Leu-OH was obtained in substantiallythe same manner as that of Preparation 2-3).

mp: 90°-93° C. Rf: 0.37 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 25-1)

N-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonyl)-L-Leu-OBzl was obtained insubstantially the same manner as that of Preparation 22-2).

mp: 67°-68° C. Rf: 0.73 (CHCl₃ :MeOH=9:1)

Preparation 25-2)

N-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonyl)-L-Leu-OH was obtained insubstantially the same manner as that of Preparation 2-3).

Rf: 0.30 (CHCl₃ :MeOH=9:1)

Preparation 26-1)

N-Neopentyl-N-ethylamin.HCl was obtained in substantially the samemanner as that of Preparation 22-1).

mp: >250° C.

Preparation 26-2)

N-(N-Neopentyl-N-ethylcarbamoyl)-L-Leu-OBzl was obtained insubstantially the same manner as that of Preparation 22-2).

Rf: 0.51

Preparation 26-3)

N-(N-Neopentyl-N-ethylcarbamoyl)-L-Leu-OH was obtained in substantiallythe same manner as that of Preparation 2-3).

Rf: 0.41 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 27-1)

To a suspension of L-norleucine benzyl ester hydrochloride (505 mg) intoluene (10 ml) was added trichloromethyl chloroformate (0.16 ml), andthe mixture was refluxed for 1 hour. Activated carbon (0.1 g) was thenadded, and the mixture was refluxed for an additional 1 hour. Afterremoval of the activated carbon by filtration, the filtrate wasconcentrated in vacuo. The crystalline residue was dissolved in ethylacetate (20 ml), and hexahydro-1H-azepine (283 mg) was added. Afterstirring for 30 minutes, the solution was washed in turn with 7%hydrochloric acid, saturated aqueous sodium bicarbonate solution, andaqueous sodium chloride solution, dried over magnesium sulfate, andconcentrated in vacuo to giveN-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Nle-OBzl (632 mg) as an oil.

Rf: 0.30 (n-hexane:EtOAc=2:1)

Preparation 27-2)

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Nle-OH was obtained insubstantially the same manner as that of Preparation 2-3).

mp: 107°-108° C. Rf: 0.44 (benzene:EtOAc:AcOH=20:20:1)

Preparation 28

[(2R)-2-(Octahydroazocin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-OEt

Rf: 0.43 (CHCl₃ :MeOH:AcOH=16:1:1)

Preparation 29

N-Piperidinocarbonyl-L-Leu-D-Trp(Me)-D-Pya-OEt

Rf: 0.44 (MeOH:CHCl₃ =1:9)

EXAMPLE 1

To a solution of (2R)-2-(piperidinocarbonylmethyl)-4-methylvaleric acid(113 mg) and H-D-Trp(Me)-D-Pya-pyrrolidineamide dihydrochloride (220 mg)in dimethylformamide (3 ml) were added HOBT (61 mg), N-methylmorpholine(46 mg), and WSCD (70 mg) at 0° C. After being stirred at roomtemperature for 20 hours, the mixture was poured into saturated aqueousammonium chloride solution, and extracted with ethyl acetate (10 ml×2).The organic layer was washed with saturated aqueous sodium bicarbonatesolution and water successively, dried over magnesium sulfate, andconcentrated in vacuo. The crystalline residue was washed with a mixtureof ethyl acetate and ethyl ether (1:1) to give(2R)-2-(piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide(106 mg).

mp: 100°-102° C. Rf: 0.43 (MeOH:CHCl₃ =1:10)

EXAMPLE 2

(2R)-2-(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamidewas obtained in substantially the same manner as that of Example 1.

mp: 119°-121° C. Rf: 0.45 (MeOH:CHCl₃ =1:10)

EXAMPLE 3

To a solution of(2R)-2-(piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide(100 mg) in chloroform (3 ml) was added 4N-hydrogen chloride in ethylacetate (0.039 ml). The solution was stirred at room temperature for 5minutes and concentrated in vacuo to give(2R)-2-(piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamidehydrochloride (106 mg) as an amorphous powder.

Rf: 0.43 (MeOH:CHCl₃ =1:10)

The following compounds were obtained in substantially the same manneras that of Example 1.

EXAMPLE 4

[(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-pyrrolidineamidehydrochloride

Rf: 0.33 (CHCl₃ :MeOH:AcOH=16:1:1)

EXAMPLE 5

[(2R)-2-(Octahydroazocin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-pyrrolidineamidehydrochloride

Rf: 0.45 (CHCl₃ :MeOH:AcOH=16:1:1), 0.41 (MeOH:CHCl₃ =1:9)

EXAMPLE 6

(2R)-2-(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamidehydrochloride was obtained in substantially the same manner as that ofExample 3.

Rf: 0.45 (MeOH:CHCl₃ =1:10)

EXAMPLE 7

Saturated aqueous sodium bicarbonate solution (5 ml) was added slowly toa suspension of H-D-Trp(Me)-D-Pya-pyrrolidineamide dihydrochloride (230mg) in chloroform (30 ml). The mixture was stirred for 10 minutes andthe organic layer was separated. The aqueous layer was extracted withchloroform (10 ml). The combined organic layer was washed with saturatedsodium chloride solution (10 ml), dried over magnesium sulfate, andconcentrated in vacuo. The residue was dissolved in DMF (3 ml). To thissolution was added(2R)-2-[N-ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleric acidsuccinimido ester (186 mg). After being stirred at room temperatureovernight, the solution was poured into saturated aqueous ammoniumchloride solution, and extracted with ethyl acetate (20 ml×2). Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution successively,dried over magnesium sulfate, and concentrated in vacuo. The crystallineresidue was washed with ethyl ether to give(2R)-2-[N-ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide(116 mg).

mp: 96°-98° C. Rf: 0.53 (MeOH:CHCl₃ =1:10)

EXAMPLE 8

(2R)-2-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamidehydrochloride was obtained in substantially the same manner as that ofExample 3.

Rf: 0.53 (MeOH:CHCl₃ =1:10)

The following compounds were obtained in substantially the same manneras that of Example 7.

EXAMPLE 9

(2R)-2-(N-Ethyl-N-isopropylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide

mp: 103°-110° C. Rf: 0.43 (MeOH:CHCl₃ =1:10)

EXAMPLE 10

(2R)-2-[N-Propyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide

mp: 93°-96° C. Rf: 0.43 (MeOH:CHCl₃ =1:10)

EXAMPLE 11

(2R)-2-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonylmethyl)4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide

mp: 97°-103° C. Rf: 0.56 (CHCl₃ :MeOH=9:1)

EXAMPLE 12

(2R)-2-(N-Neopentyl-N-ethylcarbamoylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide

mp: 106°-122° C. Rf: 0.51 (CHCl₃ :MeOH=9:1)

The following compounds were obtained in substantially the same manneras that of Example 1.

EXAMPLE 13

N-(Piperidinocarbonyl)-L-Leu-D-Trp(Me)-D-Pya-pyrrolidineamide

Rf: 0.31 (MeOH:CHCl₃ =1:9)

EXAMPLE 14

N-Octahydroazocin-1-ylcarbonyl-L-Leu-D-Trp(Me)-D-Pya-pyrrolidineamide

Rf: 0.32 (MeOH:CHCl₃ =1:9)

EXAMPLE 15

N-(Isopropyl-N-ethylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-pyrrolidineamide

Rf: 0.43 (MeOH:CHCl₃ =1:9)

EXAMPLE 16

N-[N-Propyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-pyrrolidineamide

Rf: 0.52 (MeOH:CHCl₃ =1:10)

EXAMPLE 17

N-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-pyrrolidineamide

Rf: 0.32 (MeOH:CHCl₃ =1:10)

EXAMPLE 18

N-(3-Azabicyclo[3.2.2]nonan-3-yl)carbonyl-L-Leu-D-TrP(Me)-D-Pya-pyrrolidineamide

Rf: 0.39 (MeOH:CHCl₃ =1:9)

EXAMPLE 19

N-(N-Neopentyl-N-ethylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-pyrrolidineamide

Rf: 0.57 (CHCl₃ :MeOH=9:1)

EXAMPLE 20

[(2R)-2-(1-Piperidinocarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-dimethylamidehydrochloride

Rf: 0.33 (MeOH:CHCl₃ =1:9)

EXAMPLE 21

[(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-dimethylamidehydrochloride

Rf: 0.33 (CHCl₃ :MeOH:AcOH=16:1:1)

EXAMPLE 22

[(2R)-2-(Octahydroazocin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-dimethylamidehydrochloride

Rf: 0.45 (MeOH:CHCl₃ =1:9)

EXAMPLE 23

(2R)-2-(N-Methyl-N-phenylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamidehydrochloride

Rf: 0.51 (MeOH:CHCl₃ =1:10)

EXAMPLE 24

(2R)-2-(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamide

Rf: 0.53 (MeOH:CHCl₃ =1:10)

EXAMPLE 25(2R)-2-(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamidehydrochloride was obtained in substantially the same manner as that ofExample 3.

Rf: 0.53 (MeOH:CHCl₃ =1:10)

The following compounds were obtained in substantially the same manneras that of Example 7.

EXAMPLE 26

(2R)-2-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamide

mp: 103°-105° C. Rf: 0.49 (CHCl₃ :MeOH=9:1)

EXAMPLE 27

(2R)-2-[(N-Neopentyl-N-ethylcarbamoyl)methyl]-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamide

mp: 94°-101° C. Rf: 0.51 (CHCl₃ MeOH=9:1)

EXAMPLE 28

(2R)-2-(N-Ethyl-N-isopropylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamide

mp: 96°-99° C. Rf: 0.53 (MeOH:CHCl₃ =1:10)

EXAMPLE 29

(2R)-2-[N-Propyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamide

mp: 97°-100° C. Rf: 0.50 (MeOH:CHCl₃ =1:10)

EXAMPLE 30

(2R)-2-[N-Methyl-N-(o-tolyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamidehydrochloride was obtained in substantially the same manner as that ofExample 3.

Rf: 0.53 (MeOH:CHCl₃ =1:10)

EXAMPLE 31

(2R)-2-[N-Methyl-N-(o-tolyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-dimethylamidewas obtained in substantially the same manner as that of Example 7.

mp: 105°-107° C. Rf: 0.53 (MeOH:CHCl₃ =1:10)

The following compounds were obtained in substantially the same manneras that of Example 1.

EXAMPLE 32

N-Piperidinocarbonyl-L-Leu-D-Trp(Me)-D-Pya-dimethylamide

Rf: 0.43 (MeOH:CHCl₃ =1:9)

EXAMPLE 33

N-(Octahydroazocin-1-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-dimethylamide

Rf: 0.32 (MeOH:CHCl₃ =1:9)

EXAMPLE 34

N-(N-Isopropyl-N-ethylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-dimethylamide

Rf: 0.43 (MeOH:CHCl₃ =1:9)

EXAMPLE 35

N-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-dimethylamide

Rf: 0.39 (MeOH:CHCl₃ =1:10)

EXAMPLE 36

N-(3-Azabicyclo[3.2.2]nonan-3-yl)carbonyl-L-Leu-D-Trp(Me)-D-Pya-dimethylamide

Rf: 0.30 (MeOH:CHCl₃ =1:9)

EXAMPLE 37

N-[N-Propyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-dimethylamide

Rf: 0.55 (MeOH:CHCl₃ =1:10)

EXAMPLE 38

N-(N-Neopentyl-N-ethylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-dimethylamide

Rf: 0.51 (CHCl₃ :MeOH=9:1)

EXAMPLE 39

N-Piperidinocarbonyl-L-Leu-D-Trp(Me)-D-Pya-ethylamide

Rf: 0.29 (MeOH:CHCl₃ =1:9)

EXAMPLE 40

N-Octahydroazocin-1-ylcarbonyl-L-Leu-D-Trp(Me)-D-Pya-ethylamide

Rf: 0.36 (MeOH:CHCl₃ =1:9)

EXAMPLE 41

(2R)-2-(Piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-morpholineamide

mp: 107°-110° C. Rf: 0.50 (MeOH:CHCl₃ =1:10)

EXAMPLE 42

(2R)-2-(Piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-morpholineamidehydrochloride was obtained in substantially the same manner as that ofExample 3.

Rf: 0.50 (MeOH:CHCl₃ =1:10)

The following compounds were obtained in substantially the same manneras that of Example 1.

EXAMPLE 43

[(2R)-2-(Hexahydro-1H-azepin-1-yl)carbonylmethyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-morpholineamidehydrochloride

Rf: 0.33 (CHCl₃ :MeOH:AcOH=16:1:1)

EXAMPLE 44

[(2R)-2-(Octahydroazocin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-morpholineamidehydrochloride

Rf: 0.40 (CHCl₃ :MeOH:AcOH=16:1:1)

EXAMPLE 45

(2R)-2-(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-morpholineamidehydrochloride

Rf: 0.33 (MeOH:CHCl₃ =1:10)

EXAMPLE 46

N-Piperidinocarbonyl-L-Leu-D-Trp(Me)-D-Pya-morpholineamide

Rf: 0.44 (MeOH:CHCl₃ =1:9)

EXAMPLE 47

N-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-TrP(Me)-D-Pya-morpholineamid

Rf: 0.42 (MeOH:CHCl₃ =1:10)

EXAMPLE 48

N-(Octahydroazocin-1-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-morpholineamide

Rf: 0.37 (MeOH:CHCl₃ =1:9)

EXAMPLE 49

[(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-thiomorpholineamidehydrochloride

Rf: 0.34 (CHCl₃ :MeOH:AcOH=16:1:1)

EXAMPLE 50

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-piperidineamidehydrochloride

mp: 122°-127° C. Rf: 0.60 (CHCl₃ :MeOH=9:1)

EXAMPLE 51

[(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-N',N'-dimethylhydrazidedihydrochloride

Rf: 0.36 (CHCl₃ :MeOH:AcOH=16:1:1)

EXAMPLE 52

[(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-(N-morpholino)amidehydrochloride

Rf: 0.33 (CHCl₃ :MeOH:AcOH=16:1:1)

EXAMPLE 53

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-[N-(4-methylpiperazin-1-yl)amide]trihydrochloridewas obtained from(2R)-2-(hexahydro-1H-azepin-1-ylcarbonyl)methylvaleryl-D-Trp(Me)-D-Pya-OHin substantially the same manner as that of Preparation 1-1) in thepresence of HOBT.

Rf: 0.46 (CHCl₃ :MeOH=9:1)

The following compounds were obtained from corresponding startingcompounds in substantially the same manner as that of Example 53.

EXAMPLE 54

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-ethylamidehydrochloride

Rf: 0.53 (CHCl₃ :MeOH=9:1)

EXAMPLE 55

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-2-methoxyethylamidehydrochloride

Rf: 0.52 (CHCl₃ :MeOH=9:1)

EXAMPLE 56

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-(2-morpholinoethyl)amidedihydrochloride

Rf: 0.51 (CHCl₃ :MeOH=9:1)

EXAMPLE 57

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-3-(2-oxopyrrolidin-1-yl)propylamidehydrochloride

Rf: 0.47 (CHCl₃ :MeOH=9:1)

EXAMPLE 58

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-2-(1-piperidyl)ethylamidedihydrochloride

Rf: 0.26 (CHCl₃ :MeOH=9:1)

EXAMPLE 59

(2R)-2-(Hexahydro-1H-azepin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-2-(2-pyridylethyl)amidedihydrochloride

mp: 75°-90° C. Rf: 0.34 (CHCl₃ :MeOH=9:1)

The following compounds were obtained in substantially the same manneras that of Example 7.

EXAMPLE 60

(2R)-2-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-NH₂

Rf: 0.44 (CHCl₃ :MeOH=9:1)

EXAMPLE 61

(2R)-2-(N-Neopentyl-N-ethylcarbamoylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-NH₂

Rf: 0.46 (CHCl₃ :MeOH=9:1)

EXAMPLE 62

(2R)-2-(N-Ethyl-N-isopropylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-NH₂

Rf: 0.37 (MeOH:CHCl₃ =1:10)

EXAMPLE 63

(2R)-2-[N-Propyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-NH₂

Rf: 0.39 (MeOH:CHCl₃ =1:10)

EXAMPLE 64

N-Piperidinocarbonyl-L-Leu-D-Trp(Me)-D-Pya-NH₂ was obtained insubstantially the same manner as that of Example 1.

Rf: 0.18 (MeOH:CHCl₃ =1:9)

EXAMPLE 65

[(2R)-2-(Piperidinocarbonyl)methyl-4-methylvaleryl]-D-TrP(Me)-D-Pya-NH.sub.2hydrochloride was obtained from(2R)-2-(carboxymethyl)-4-methylvaleryl]-D-Trp(Me)-D-Pya-NH₂hydrochloride in substantially the same manner as that of Example 1.

Rf: 0.53 (CHCl₃ :MeOH:AcOH=8:1:1)

The following compounds were obtained in substantially the same manneras that of Example 65.

EXAMPLE 66

[(2R)-2-(N,N-Dipropylcarbamoyl)methyl-4-methylvaleryl]-D-TrP(Me)-D-Pya-NH.sub.2hydrochloride

Rf: 0.69 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 67

[(2R)-2-(N-Butyl-N-methylcarbamoyl)methyl-4-methylvaleryl]-D-TrP(Me)-D-Pya-NH₂hydrochloride

Rf: 0.61 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 68

[(2R)-2-(Octahydroazocin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-TrP(Me)-D-Pya-NH₂hydrochloride mp: 119°-123° C.

Rf: 0.70 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 69

(2R)-2-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-NH₂hydrochloride

Rf: 0.40 (MeOH:CHCl₃ =1:10)

EXAMPLE 70

(2R)-2-(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-NH₂hydrochloride

Rf: 0.53 (MeOH:CHCl₃ =1:10)

EXAMPLE 71

(2R)-2-(4-Methylpiperidinocarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-NH₂hydrochloride

Rf: 0.53 (MeOH:CHCl₃ =1:10)

EXAMPLE 72

(2R)-2-(Indolin-1-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-NH.sub.2hydrochloride

Rf: 0.49 (MeOH:CHCl₃ =1:10)

EXAMPLE 73

(2R)-2-(N-Ethyl-N-butylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-NH.sub.2hydrochloride

Rf: 0.43 (MeOH:CHCl₃ =1:10)

EXAMPLE 74

N-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-OEt (100mg) was dissolved in 5.3N ammonia in methanol (5 ml). The solution wasallowed to stand at room temperature for 2 days and concentrated invacuo to giveN-[N-ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-NH₂ (95 mg)as an amorphous powder.

Rf: 0.41 (MeOH:CHCl₃ =1:10)

The following compounds were obtained in substantially the same manneras that of Example 74.

EXAMPLE 75

N-[N-Propyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-NH₂

Rf: 0.38 (MeOH:CHCl₃ =1:10)

EXAMPLE 76

N-(Octahydroazocin-1-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-NH₂

mp: 105°-110° C. Rf: 0.45 (CHCl₃ :MeOH=9:1)

EXAMPLE 77

N-(N-Neopentyl-N-ethylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-NH₂

mp: 95°-100° C. Rf: 0.44 (CHCl₃ :MeOH=9:1)

EXAMPLE 78

N-[(1S)-{1-(Dimethylcarbamoyl)-2,2-dimethylpropyl}carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-NH₂

mp: 226°-227° C. Rf: 0.23 (MeOH:CHCl₃ =1:10)

EXAMPLE 79

N-Piperidinocarbonyl-L-Leu-D-Trp(Me)-D-Pya-methylamide

Rf: 0.41 (MeOH:CHCl₃ =1:9)

EXAMPLE 80

N-(Octahydroazocin-1-yl)-L-Leu-D-Trp(Me)-D-Pya-methylamide

mp: 169°-172° C. Rf: 0.56 (CHCl₃ :MeOH=9:1)

EXAMPLE 81

N-(N-Neopentyl-N-ethylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-methylamide

Rf: 0.55 (CHCl₃ :MeOH=9:1)

EXAMPLE 82

(2R)-2-(N-Methyl-N-phenylcarbamoyl)methyl-4-methylvaleryl-D-TrP(Me)-D-Pya-NH₂hydrochloride was obtained in substantially the same manner as that ofExample 3.

Rf: 0.41 (MeOH:CHCl₃ =1:10)

EXAMPLE 83

[(2R)-2-(1,2,3,4-Tetrahydroquinolin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-TrP(Me)-D-Pya-NH₂hydrochloride was obtained in substantially the same manner as that ofExample 74.

Rf: 0.26 (MeOH:CHCl₃ =1:9)

EXAMPLE 84

(2R)-2-(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-methylamidehydrochloride was obtained in substantially the same manner as that ofExample 3.

Rf: 0.38 (MeOH:CHCl₃ =1:10)

The following compounds were obtained in substantially the same manneras that of Example 74.

EXAMPLE 85

[(2R)-2-(Piperidinocarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-methylaminohydrochloride

Rf: 0.40 (MeOH:CHCl₃ =1:9)

EXAMPLE 86

[(2R)-2-(Octahydroazocin-1-ylcarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-methylamidehydrochloride

Rf: 0.38 (MeOH:CHCl₃ =1:9)

EXAMPLE 87

(2R)-2-(N-Methyl-N-phenylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-NH₂

Rf: 0.41 (MeOH:CHCl₃ =1:10)

EXAMPLE 88

(2R)-2-(N-Methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-methylamide

Rf: 0.38 (MeOH:CHCl₃ =1:10)

EXAMPLE 89

1N Aqueous sodium hydroxide solution (0.3 ml) was added to a solution of(2R)-2-[N-ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-OEt(72 mg) in ethanol (1 ml). After being stirred at room temperature for10 minutes, 1N hydrochloric acid (0.3 ml) was added to the solution andthe solvent was evaporated in vacuo. The residue was dissolved in ethylacetate (20 ml), washed with saturated aqueous sodium chloride solution,dried over magnesium sulfate, and evaporated in vacuo. The residue (64mg) was dissolved in sodium hydroxide solution (0.103 mmol in 10 mlwater) and lyophilized to give(2R)-2-[N-ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-ONa(66 mg) as a white powder.

Rf: 0.58 (CHCl₃ :MeOH:AcOH=8:1:1)

The following compounds were obtained in substantially the same manneras that of Example 89.

EXAMPLE 90

N-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-ONa

Rf: 0.30 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 91

N-(Hexahydro-1H-azepin-1-ylcarbonyl)-L-Nle-D-Trp(Me)-D-Pya-ONa

Rf: 0.66 (CHCl₃ :MeOH:AcOH=8:2:1)

EXAMPLE 92

N-[N-Propyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-ONa

Rf: 0.32 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 93

N-(N-Ethyl-N-isopropylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-ONa

Rf: 0.26 (CHCl₃ :MeOH:AcOH=8:1:1)

The following compounds were obtained in substantially the same manneras that of Example 1.

EXAMPLE 94

[(2R)-2-(1,2,3,4-Tetrahydroquinolin-1-ylcarbonyl)-methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-OEt

Rf: 0.41 (CHCl₃ :MeOH:AcOH=16:1:1), 0.72 (MeOH:CHCl₃ =1:9)

EXAMPLE 95

[(2R)-2-(Piperidinocarbonyl)methyl-4-methylvaleryl]-D-Trp(Me)-D-Pya-OEt

Rf: 0.43 (CHCl₃ :MeOH:AcOH=16:1:1)

EXAMPLE 96

(2R)-2-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-OEt

mp: 61°-63° C. Rf: 0.33 (MeOH:CHCl₃ =1:20)

EXAMPLE 97

(2R)-2-(N-Methyl-N-phenylcarbamoylmethyl-4-methylvaleryl-D-Trp(Me)-D-Pya-OEt

Rf: 0.38 (MeOH:CHCl₃ =1:20)

EXAMPLE 98

N-[N-Propyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-OEt

Rf: 0.46 (EtOAc only)

EXAMPLE 99

N-[N-Ethyl-N-(1-ethylpropyl)carbamoyl]-L-Leu-D-Trp(Me)-D-Pya-OEt

Rf: 0.44 (EtOAc only)

EXAMPLE 100

N-(N-Isopropyl-N-ethylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-OEt

Rf: 0.63 (CHCl₃ :MeOH=9:1)

EXAMPLE 101

N-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-OEt

Rf: 0.66 (CHCl₃ :MeOH=9:1)

EXAMPLE 102

N-(N-Neopentyl-N-ethylcarbamoyl)-L-Leu-D-Trp(Me)-D-Pya-OEt

Rf: 0.62 (CHCl₃ :MeOH=9:1)

EXAMPLE 103

N-(Hexahydro-1H-azepin-1-ylcarbonyl-L-Nle-D-Trp(Me)-D-Pya-OEt

Rf: 0.52 (MeOH:CHCl₃ =1:10)

EXAMPLE 104

To a solution of(2R)-2-(N-methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleric acid (174mg) in dichloromethane (5 ml) were added oxalyl chloride (0.067 ml) andtrace of dimethylformamide. After being stirred at room temperature for1 hour, a solution of H-D-Trp(Me)-D-Pya-OEt dihydrochloride (300 mg) andN-methylmorpholine (197 mg) in dichloromethane (3 ml) was added to thesolution. After being stirred at room temperature for 30 minutes, thesolvent was evaporated in vacuo. The residue was dissolved in ethylacetate (20 ml), washed with saturated aqueous ammonium chloridesolution, saturated aqueous sodium bicarbonate solution, and saturatedaqueous sodium chloride solution successively, dried over magnesiumsulfate, and evaporated in vacuo. The residue was purified with silicagel column chromatography (MeOH:CHCl₃ =1:100 as an eluent) to give(2R)-2-(N-methyl-N-cyclohexylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-OEt(82 mg).

EXAMPLE 105

Rf: 0.47 (MeOH:CHCl₃ =1:20)

(2R)-2-(N-Ethyl-N-isopropylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-OEtwas obtained in substantially the same manner as that of Example 7.

Rf: 0.30 (CHCl₃ :MeOH=20:1)

EXAMPLE 106

(2R)-2-(Piperidinocarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-ONawas obtained in substantially the same manner as that of Example 89.

Rf: 0.40 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 107

(2R)-2-[N-Propyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-ONawas obtained in substantially the same manner as that of Example 89.

Rf: 0.58 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 108

(2R)-2-[N-Propyl-N-(1-ethylpropyl)carbamoyl]methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-OEtwas obtained in substantially the same manner as that of Example 7.

Rf: 0.36 (CHCl₃ :MeOH=20:1)

EXAMPLE 109

(2R)-2-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-ONawas obtained in substantially the same manner as that of Example 89.

Rf: 0.58 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 110

(2R)-2-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-OEtwas obtained in substantially the same manner as that of Example 7.

Rf: 0.38 (CHCl₃ :MeOH=20:1)

EXAMPLE 111

N-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-methylamidewas obtained in substantially the same manner as that of Example 74.

mp: 144°-156° C. Rf: 0.62 (CHCl₃ :MeOH=9:1)

EXAMPLE 112

N-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-NH₂ wasobtained in substantially the same manner as that of Example 74.

mp: 125°-130° C. Rf: 0.54 (CHCl₃ :MeOH=9:1)

EXAMPLE 113

N-(3-Azabicyclo[3.2.2]nonan-3-ylcarbonyl)-L-Leu-D-Trp(Me)-D-Pya-ONa wasobtained in substantially the same manner as that of Example 89.

Rf: 0.35 (CHCl₃ :MeOH:AcOH=8:1:1)

EXAMPLE 114

(2R)-2-(N-Ethyl-N-isopropylcarbamoyl)methyl-4-methylvaleryl-D-Trp(Me)-D-Pya-ONawas obtained in substantially the same manner as that of Example 89.

Rf: 0.50 (CHCl₃ :MeOH:AcOH 8:1:1)

The following compounds were obatined in substantially the same manneras tht of Example 65.

EXAMPLE 115

(2R)-2-(piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide

Rf: 0.43 (MeOH:CHCl₃ =1:10)

EXAMPLE 116

(2R)-2-(piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamidehydrochloride

Rf: 0.43 (MeOH:CHCl₃ =1:10)

The following compounds were obatined in substantially the same manneras tht of Example 74.

EXAMPLE 117

(2R)-2-(piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamide

Rf: 0.43 (MeOH:CHCl₃ =1:10)

EXAMPLE 118

(2R)-2-(piperidinocarbonylmethyl)-4-methylvaleryl-D-Trp(Me)-D-Pya-pyrrolidineamidehydrochloride

Rf: 0.43 (MeOH:CHCl₃ =1:10)

We claim:
 1. A compound of the formula: ##STR6## in which R³ is hydrogenor lower alkyl, R⁴ is pyridyl(lower)alkyl; andR¹ is C₃ -C₈alkyleneamino, N,N-di(lower)alkylamino, N-lower alkyl-N-arylamino,N-lower alkyl-N-C₃ -C₈ cycloalkylamino, or C₅ -C₁₀ bicyclicalkyleneamino, R² is lower alkyl, R⁵ is C₃ -C₈ alkyleneamino,N,N-di(lower)alkylamino, morpholino, thiomorpholino,N',N'-di(lower)alkylhydrazino, morpholinoamino, loweralkylpiperazinylamino, lower alkoxy(lower)alkylamino,morpholino(lower)alkylamino, C₃ -C₈ alkyleneamino(lower)alkylamino whichmay be substituted by oxo, or pyridyl(lower)alkylamino, and A is loweralkylene; or R¹ is piperidin-1-yl, lower alkylpiperidin-1-yl,octahydroazocin-1-yl, indolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl,N,N-di(lower)alkylamino, N-lower alkyl-N-arylamino, N-lower alkyl-N-C₃-C₈ cycloalkylamino, or C₅ -C₁₀ bicyclic alkyleneamino, R² is loweralkyl, R⁵ is amino or lower alkylamino, and A is lower alkylene; or R¹is piperidin-1-yl, octahydroazocin-1-yl, N,N-di(lower)alkylamino, or C₅-C₁₀ bicyclic alkyleneamino, R² is lower alkyl, R⁵ is amino, loweralkylamino, N,N-di(lower)alkylamino, C₃ -C₈ alkyleneamino, ormorpholino, and A is --NH--; or R¹ is hexahydro-1H-azepin-1-yl, R² isisobutyl, R⁵ is ethylamino, and A is methylene; or R¹ isN-[1-(dimethylcarbamoyl)-2,2-dimethylpropyl]amino, R² is isobutyl, R⁵ isamino, and A is --NH--; or R¹ is N,N-di(lower)alkylamino,1,2,3,4-tetrahydroquinolin-1-yl, N-lower alkyl-N-arylamino, or N-loweralkyl-N-C₃ -C₈ cycloalkylamino, R² is lower alkyl, R⁵ is hydroxy orCO--R⁵ is lower alkoxycarbonyl, and A is lower alkylene; or R¹ is C₅-C₁₀ bicyclic alkyleneamino, R² is lower alkyl, R⁵ is hydroxy or CO--R⁵is lower alkoxycarbonyl, and A is lower alkylene or --NH--; or R¹ isN-ethyl-N-(1-ethylpropyl)amino, N-ethyl-N-isopropylamino,N-ethyl-N-neopentylamino, or N-(1-ethylpropyl)-N-propylamino, R² isisobutyl, R⁵ is hydroxy or CO--R⁵ is lower alkoxycarbonyl, and A is--NH--; or R¹ is piperidin-1-yl, R² is isobutyl, R⁵ is hydroxy or CO--R⁵is lower alkoxycarbonyl, and A is methylene; or R¹ ishexahydro-1H-azepin-1-yl, R² is propyl, R⁵ is hydroxy or CO--R⁵ is loweralkoxycarbonyl, and A is --NH--;or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, whereinR³ is methyl, and R⁴ is2-pyridylmethyl.
 3. The compound of claim 2 having the followingformula: ##STR7## wherein R² is isobutyl, R⁵ is pyrrolidin-1-yl, A ismethylene, and R¹ is piperidino, hexahydro-1H-azepin-1-yl,octahydroazocin-1-yl, N-methyl-N-cyclohexylamino,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl orN-neopentyl-N-ethylamino; orR² is isobutyl R⁵ is pyrrolidin-1-yl, A is--NH--, and R¹ is piperidino, octahydroazocin-1-yl,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl orN-neopentyl-N-ethylamino; or R² is isobutyl, R⁵ is dimethylamino, A ismethylene, and R¹ is piperidino, hexahydro-1H-azepin-1-yl,octahydroazocin-1-yl, N-methyl-N-phenylamino,N-methyl-N-cyclohexylamino, N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl,N-neopentyl-N-ethylamino or N-methyl-N-(o-tolyl)amino; or R² isisobutyl, R⁵ is dimethylamino, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl, N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl, or N-neopentyl-N-ethylamino; or R¹ ishexahydro-1H-azepin-1-yl, R² is isobutyl, R⁵ is ethylamino and A ismethylene; or R² is isobutyl, R⁵ is morpholino, A is methylene, and R¹is piperidino, hexahydro-1H-azepin-1-yl, octahydroazocin-1-yl orN-methyl-N-cyclohexylamino; or R² is isobutyl, R⁵ is morpholino, A is--NH--, and R¹ is piperidino, octahydroazocin-1-yl orN-ethyl-N-(1-ethylpropyl)amino; or R¹ is hexahydro-1H-azepin-1-yl, R² isisobutyl, A is methylene, and R⁵ is thiomorpholino, piperidino,N',N'-dimethylhydrazino, morpholinoamino, 4-methylpiperazin-1-ylamino,ethylamino, 2-methoxyethylamino, 2-morpholinoethylamino,3-(2-oxopyrrolidin-1-yl)- propylamino, 2-piperidinoethylamino or2-(pyridin-2-yl)ethylamino; or R² is isobutyl, R⁵ is amino, A ismethylene, and R¹ is piperidino, octahydroazocin-1-yl, dipropylamino,N-methyl-N-butylamino, N-ethyl-N-butylamino, N-ethyl-N-isopropylamino,N-ethyl-N-(1-ethylpropyl)amino, N-propyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl, N-ethyl-N-neopentylamino,N-methyl-N-cyclohexylamino, N-methyl-N-phenylamino,1,2,3,4-tetrahydroquinolin-1-yl, 4-methylpiperidino or indolin-1-yl; orR² is isobutyl, R⁵ is amino, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl, N-ethyl-N-(1-ethylpropyl)amino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-neopentylamino,(1-dimethylcarbamoyl-2,2-dimethylpropyl)amino or3-azabicyclo[3.2.2]nonan-3-yl; R² is isobutyl, R⁵ is methylamino, A is--NH--, and R is piperidino, octahydroazocin-1-yl,N-ethyl-N-neopentylamino or 3-azabicyclo[3.2.2]nonan-3-yl; or R² isisobutyl, R⁵ is methylamino, A is methylene, and R¹ is piperidino,octahydroazocin-1-yl or N-methyl-N-cyclohexylamino; R² is isobutyl, R⁵is hydroxy, A is methylene, and R¹ is piperidino,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino or 3-azabicyclo[3.2.2]nonan-3-yl; or R²is isobutyl, R⁵ is hydroxy, A is --NH--, and R¹ isN-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino or 3-azabicyclo[3.2.2]nonan-3-yl; or R¹is hexahydro-1H-azepin-1-yl, R² is propyl, R⁵ is hydroxy and A is--NH--; or R² is isobutyl, R⁵ is ethoxy, A is methylene, and R¹ ispiperidino, N-methyl-N-cyclohexylamino, N-methyl-N-phenylamino,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl or1,2,3,4-tetrahydroquinolin-1-yl; or R² is isobutyl, R⁵ is ethoxy, A is--NH--, and R¹ is N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl or N-neopentyl-N-ethylamino; or R¹ ishexahydro-1H-azepin-1-yl, R² is propyl, R⁵ is ethoxy and A is --NH--. 4.The compound of claim 3, whereinR² is isobutyl, R⁵ is pyrrolidin-1-yl, Ais methylene, and R¹ is piperidino, hexahydro-1H-azepin-1-yl,octahydroazocin-1-yl, N-methyl-N-cyclohexylamino,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl orN-neopentyl-N-ethylamino.
 5. The compound of claim 3, whereinR² isisobutyl R is pyrrolidin-1-yl, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl, N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl or N-neopentyl-N-ethylamino.
 6. Thecompound of claim 3, whereinR² is isobutyl, R⁵ is dimethylamino, A ismethylene, and R¹ is piperidino, hexahydro-1H-azepin-1-yl,octahydroazocin-1-yl, N-methyl-N-phenylamino,N-methyl-N-cyclohexylamino, N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl,N-neopentyl-N-ethylamino or N-methyl-N-(o-tolyl)amino.
 7. The compoundof claim 3, whereinR² is isobutyl, R⁵ is dimethylamino, A is --NH--, andR¹ is piperidino, octahydroazocin-1-yl, N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl, or N-neopentyl-N-ethylamino.
 8. Thecompound of claim 3, whereinR² is isobutyl, R⁵ is ethylamino, A is--NH--, and R¹ is piperidino or octahydroazocin-1-yl.
 9. The compound ofclaim 3, whereinR² is isobutyl, R⁵ is morpholino, A is methylene, and R¹is piperidino, hexahydro-1H-azepin-1-yl, octahydroazocin-1-yl orN-methyl-N-cyclohexylamino.
 10. The compound of claim 3, whereinR² isisobutyl, R⁵ is morpholino, A is --NH--, and R¹ is piperidino,octahydroazocin-1-yl or N-ethyl-N-(1-ethylpropyl)amino.
 11. The conpoundof claim 3, whereinR¹ is hexahydro-1H-azepin-1-yl, R² is isobutyl, A ismethylene, and R⁵ is thiomorpholino, piperidino,N',N'-dimethylhydrazino, morpholinoamino, 4-methylpiperazin-1-ylamino,ethylamino, 2-methoxyethylamino, 2-morpholinoethylamino,3-(2-oxopyrrolidin-1-yl)-propylamino, 2-piperidinoethylamino or2-(pyridin-2-yl)ethylamino.
 12. The compound of claim 3, whrereinR² isisobutyl, R⁵ is amino, A is methylene, and R¹ is piperidino,octahydroazocin-1-yl, dipropylamino, N-methyl-N-butylamino,N-ethyl-N-butylamino, N-ethyl-N-isopropylamino,N-ethyl-N-(1-ethylpropyl)amino, N-propyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl, N-ethyl-N-neopentylamino,N-methyl-N-cyclohexylamino, N-methyl-N-phenylamino,1,2,3,4-tetrahydroquinolin-1-yl, 4-methylpiperidino or indolin-1-yl. 13.The compound of claim 3, whereinR² is isobutyl, R⁵ is amino, A is--NH--, and R¹ is piperidino, octahydroazocin-1-yl,N-ethyl-N-(1-ethylpropyl)amino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-neopentylamino, (1-dimethylcarbamoyl-2,2-dimethylpropyl)aminoor 3-azabicyclo[3.2.2]nonan-3-yl.
 14. The compound of claim 3,wwhereinR² is isobutyl, R⁵ is methylamino, A is --NH--, and R¹ ispiperidino, octahydroazocin-1-yl, N-ethyl-N-neopentylamino or3-azabicyclo[3.2.2]nonan-3-yl.
 15. The compound of claim 3, whereinR² isisobutyl, R⁵ is methylamino, A is methylene, and R¹ is piperidino,octahydroazocin-1-yl or N-methyl-N-cyclohexylamino.
 16. The compound ofclaim 3, whereinR² is isobutyl, R⁵ is hydroxy, A is methylene, and R¹ ispiperidino, N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino or 3-azabicyclo[3.2.2]nonan-3-yl.
 17. Thecompound of claim 3, whereinR² is isobutyl, R⁵ is hydroxy, A is --NH--,and R¹ is N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino or 3-azabicyclo[3.2.2]nonan-3-yl.
 18. Thecompound of claim 3, whereinR¹ is hexahydro-1H-azepin-1-yl, R² ispropyl, R⁵ is hydroxy and A is --NH--.
 19. The compound of claim 3,whereinR² is isobutyl, R⁵ is ethoxy, A is methylene, and R¹ ispiperidino, N-methyl-N-cyclohexylamino, N-methyl-N-phenylamino,N-ethyl-N-isopropylamino, N-propyl-N-(1-ethylpropyl)amino,N-ethyl-N-(1-ethylpropyl)amino, 3-azabicyclo[3.2.2]nonan-3-yl or1,2,3,4-tetrahydroquinolin-1-yl.
 20. The compound of claim 3, whereinR²isobutyl, R⁵ is ethoxy, A is --NH--, and R¹ is N-ethyl-N-isopropylamino,N-propyl-N-(1-ethylpropyl)amino, N-ethyl-N-(1-ethylpropyl)amino,3-azabicyclo[3.2.2]nonan-3-yl or N-neopentyl-N-ethylamino.
 21. Thecompound of claim 3, whereinR¹ is hexahydro-1H-azepin-1-yl, R² ispropyl, R⁵ is ethoxy and A is --NH--.
 22. A process for the preparationof a compound of the formula: ##STR8## in which R³ is hydrogen or loweralkyl, R⁴ is pyridyl(lower)alkyl; andR¹ is C₃ -C₈ alkyleneamino,N,N-di(lower)alkylamino, N-lower alkyl-N-arylamino, N-lower alkyl-N-C₃-C₈ cycloalkylamino, or C₅ -C₁₀ bicyclic alkyleneamino, R² is loweralkyl, R⁵ is C₃ -C₈ alkyleneamino, N,N-di(lower)alkylamino, morpholino,thiomorpholino, N',N'-di(lower)alkylhydrazino, morpholinoamino, loweralkylpiperazinylamino, lower alkoxy(lower)alkylamino,morpholino(lower)alkylamino, C₃ -C₈ alkeneamino(lower)alkylamino whichmay be substituted by oxo, or pyridyl(lower)alkylamino, and A is loweralkylene; or R¹ is piperidin-1-yl, lower alkylpiperidin-1-yl,octahydroazocin-1-yl, indolin-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl,N,N-di(lower)alkylamino, N-lower alkyl-N-arylamino, N-lower alkyl-N-C₃-C₈ cycloalkylamino, or C₅ -C₁₀ bicyclic alkyleneamino, R² is loweralkyl, R⁵ is amino or lower alkylamino, and A is lower alkylene; or R¹is piperidin-1-yl, octahydroazocin-1-yl, N,N-di(lower)alkylamino, or C₅-C₁₀ bicyclic alkyleneamino, R² is lower alkyl, R⁵ is amino, loweralkylamino, N,N-di(lower)alkylamino, C₃ -C₈ alkyleneamino, ormorpholino, and A is --NH--; or R¹ is hexahydro-1H-azepin-1-yl, R² isisobutyl, R⁵ is ethylamino, and A is methylene; or R¹ isN-[1-(dimethylcarbamoyl)-2,2-dimethylpropyl]amino, R² is isobutyl, R⁵ isamino, and A is --NH--; or R¹ is N,N-di(lower)alkylamino,1,2,3,4-tetrahydroquinolin-1-yl, N-lower alkyl-N-arylamino, or N-loweralkyl-N-C₃ -C₈ cycloalkylamino, R² is lower alkyl, R⁵ is hydroxy orCO--R⁵ is lower alkoxycarbonyl, and A is lower alkylene; or R¹ is C₅-C₁₀ bicyclic alkyleneamino, R² is lower alkyl, R⁵ is hydroxy or CO--R⁵is lower alkoxycarbonyl, and A is lower alkylene or --NH--; or R¹ isN-ethyl-N-(1-ethylpropyl)amino, N-ethyl-N-isopropylamino,N-ethyl-N-neopentylamino, or N-(1-ethylpropyl)-N-propylamino, R² isisobutyl, R⁵ is hydroxy or CO--R⁵ is lower alkoxycarbonyl, and A is--NH--; or R¹ is piperidin-1-yl, R² is isobutyl, R⁵ is hydroxy or CO--R⁵is lower alkoxycarbonyl, and A is methylene; or R¹ ishexahydro-1H-azepin-1-yl, R is propyl, R⁵ is hydroxy or CO--R⁵ is loweralkoxycarbonyl, and A is --NH--;or a salt thereof, which comprises (a)reacting a compound of the formula: ##STR9## wherein R¹, R² and A areeach as defined above or its reactive derivative at the carboxy group ora salt thereof, with a compound of the formula: ##STR10## wherein R³, R⁴and R⁵ are each as defined above or its reactive derivative at the aminogroup, or a salt thereof, to give a compound of the formula: ##STR11##wherein R¹, R², R³, R⁴, R⁵ and A are each as defined above,or a saltthereof; or (b) reacting a compound of the formula: ##STR12## whereinR², R³, R⁴, R⁵ and A are each as defined above,or its reactivederivative at the carboxy group, or a salt thereof, with a compound ofthe formula:

    R.sup.1 --H                                                (IV)

wherein R¹ is as defined above, or its reactive derivative at the aminoor imino group, or a salt thereof, to give a compound of the formula:##STR13## wherein R¹, R², R³, R⁴, R⁵ and A are each as defined above, ora salt thereof; or (c) subjecting a compound of the formula: ##STR14##wherein R¹, R², R³, R⁴ and A are each as defined above, and CO--R_(a) ⁵is protected carboxy or a salt thereof, to a removal reaction of thecarboxy-protective group to give a compound of the formula: ##STR15##wherein R¹, R², R³, R⁴ and A are each as defined above,or a saltthereof; or (d) subjecting a compound of the formula: ##STR16## in whichR¹, R², R³, R⁴ and A are each as defined above, and CO--R_(b) ⁵ iscarboxy or protected carboxy, or a salt thereof, with a compound of theformula:

    R.sub.c.sup.5 --H                                          (XII)

in which R_(c) ⁵ is C₃ -C₈ alkyleneamino N,N-di(lower)alkylamino,morpholino, thiomorpholino, N',N'-di(lower)alkylhydrazino,morpholinoamino, lower alkylpiperazinylamino, loweralkoxy(lower)alkylamino, morpholino(lower)alkylamino, C₃ -C₈alkyleneamino(lower)alkylamino which may be substituted by oxo,pyridyl(lower)alkylamino, amino or lower alkylamino, to give a compoundof the formula: ##STR17## in which R¹, R², R³, R⁵ and A are each asdefined above, or a salt thereof.
 23. A pharmaceutical composition whichcomprises a compound of claim 1 or a pharmaceutically acceptable saltthereof and a pharmaceutically acceptable carrier or excipient.
 24. Amethod for treating endothelin mediated diseases which comprisesadministering a compound of claim 1 or pharmaceutically acceptable saltsthereof to human being or animals.